title: 5-hydroxytryptamine type 3 receptor modulates opioid-induced hyperalgesia and tolerance in mice.
abstract: BACKGROUND
  Opioid-induced hyperalgesia (OIH) and tolerance are challenging maladaptations associated with opioids in managing pain. Recent genetic studies and the existing literature suggest the 5-hydroxytryptamine type 3 (5-HT3) receptor participates in these phenomena. The location of the relevant receptor populations and the interactions between the 5-HT3 system and other systems controlling OIH and tolerance have not been explored, however. We hypothesized that 5-HT3 receptors modulate OIH and tolerance, and that this modulation involves the control of expression of multiple neurotransmitter and receptor systems.
  
  
  METHODS
  C57BL/6 mice were exposed to a standardized 4-day morphine administration protocol. The 5-HT3 antagonist ondansetron was administered either during or after the conclusion of morphine administration. Mechanical testing was used to quantify OIH, and thermal tail-flick responses were used to measure morphine tolerance. In other experiments spinal cord and dorsal root ganglion tissues were harvested for analysis of messenger RNA concentrations by real-time polymerase chain reaction or immunochemistry analysis.
  
  
  RESULTS
  The results showed that (1) systemic or intrathecal injection of ondansetron significantly prevented and reversed OIH, but not local intraplantar injection; (2) systemic or intrathecal injection of ondansetron prevented and reversed tolerance; and (3) ondansetron blocked morphine-induced increases of multiple genes relevant to OIH and tolerance in dorsal root ganglion and spinal cord.
  
  
  CONCLUSIONS
  Morphine acts via a 5-HT3-dependent mechanism to support multiple maladaptations to the chronic administration of morphine. Furthermore, the use of 5-HT3 receptor antagonists may provide a new avenue to prevent or reverse OIH and tolerance associated with chronic opioid use.
authors.affiliation: Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System and Stanford University, Palo Alto, California 94304, USA. dyliang@stanford.edu
authors.forename: De-Yong
authors.initials: DY
authors.lastname: Liang
authors.forename: XiangQi
authors.initials: X
authors.lastname: Li
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D004361:Drug Tolerance; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000009:adverse effects*; D017294:Ondansetron / Q000008:administration & dosage*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012702:Serotonin Antagonists / Q000008:administration & dosage*
chemical_list: D000701:Analgesics, Opioid; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D017294:Ondansetron; D009020:Morphine